Impotence is the consistent inability to achieve or sustain an erection of sufficient rigidity for sexual intercourse. It has recently been estimated that approximately 10 million American men are impotent (R. Shabsigh et al., "Evaluation of Erectile Impotence," Urology 32:83-90 (1988); W. L. Furlow, "Prevalence of Impotence in the United States," Med. Aspects Hum. Sex. 19:13-6 (1985)). Impotence is recognized to be an age-dependent disorder, with an incidence of 1.9 percent at 40 years of age and 25 percent at 65 years of age (A. C. Kinsey et al., "Age and Sexual Outlet," in Sexual Behavior in the Human Male; A. C. Kinsey et al., eds., Philadelphia, Pa.: W. B. Saunders, 218-262 (1948)). In 1985 in the United States, impotence accounted for more than several hundred thousand outpatient visits to physicians (National Center for Health Statistics, National Hospital Discharge Survey, 1985, Bethesda, Md., Department of Health and Human Services, 1989 DHHS publication no. 87-1751). Depending on the nature and cause of the problem, treatments include psychosexual therapy, hormonal therapy, administration of vasodilators such as nitroglycerin and .alpha.-adrenergic blocking agents (".alpha.-blockers"), oral administration of other pharmaceutical agents, vascular surgery, implanted penile prostheses, vacuum constriction devices and external aids such as penile splints to support the penis or penile constricting rings to alter the flow of blood through the penis.
A number of causes of impotence have been identified, including vasculogenic, neurogenic, endocrinologic and psychogenic. Vasculogenic impotence, which is caused by alterations in the flow of blood to and from the penis, is thought to be the most frequent organic cause of impotence. Common risk factors for vasculogenic impotence include hypertension, diabetes, cigarette smoking, pelvic trauma, and the like. Neurogenic impotence is associated with spinal-cord injury, multiple sclerosis, peripheral neuropathy caused by diabetes or alcoholism and severance of the autonomic nerve supply to the penis consequent to prostate surgery. Erectile dysfunction is also associated with disturbances in endocrine function resulting in low circulating testosterone levels and elevated prolactin levels.
Impotence can also be a side effect of various classes of drugs, in particular, those that interfere with central neuroendocrine control or local neurovascular control of penile smooth muscle. Krane et al., New England Journal of Medicine 321:1648 (1989). Penile erection requires (1) dilation of the arteries that regulate blood flow to the lacunae of the corpora cavernosum, (2) relaxation of trabecular smooth muscle, which facilitates engorgement of the penis with blood, and (3) compression of the venules by the expanding trabecular walls to decrease venous outflow.
Trabecular smooth muscle tone is controlled locally by adrenergic (constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic (dilator) innervation, and by endothelium-derived vasoactive substances such as vasoactive intestinal polypeptide (VIP), prostanoids, endothelin and nitric oxide. High sympathetic tone (noradrenergic) is implicated in erectile dysfunction, and, in some patients, the disorder can be successfully treated with noradrenergic receptor antagonists. See, e.g., Krane et al., supra.
There is also evidence that dopaminergic mechanisms are involved in erectile function. For example, pharmacologic agents that elevate the level of brain dopamine or stimulate brain dopamine receptors increase sexual activity in animals (see, e.g., Gessa & Tagliamonte, Life Sciences 14:425 (1974); Da Prada et al., Brain Research 57:383 (1973)).
Administration of L-DOPA, a dopamine precursor, enhances sexual activity in male rats. L-DOPA has been used in the treatment of Parkinsonism and is known to act as an aphrodisiac in some patients (Gessa & Tagliamonte, supra; Hyppa et al., Acta Neurologic Scand. 46:223 (Supp. 43, 1970)). Specific dopamine agonists have been studied for their effects on erectile function. Apomorphine, (n-propyl)norapo-morphine, bromocryptine, amantidine, fenfluramine, L-DOPA and various other pharmacological activators of central dopaminergic receptors have been found to increase episodes of penile erection in male rats (Benassi-Benelli et al., Arch. int. Pharmacodyn. 242:241 (1979); Poggioli et al., Riv. di Farm. & Terap. 9:213 (1978); Falaschi et al., Apomorphine and Other Dopaminomimetics, 1:117-121 (Gessa & Corsini, Eds., Raven Press, N.Y.)). In addition, U.S. Pat. No. 4,521,421 to Foreman relates to the oral or intravenous administration of quinoline compounds to treat sexual dysfunction in mammals.
The currently available dopamine agonists, with few exceptions, have found limited use in the treatment of erectile dysfunction because of their peripheral side effects. These effects include nausea and vomiting, postural hypotension, arrhythmias, tachycardia, dysphoria, psychosis, hallucinations, drowsiness and dyskinesias (See, e.g., Martindale The Extra Pharmacopoeia, 31st Ed., pages 1151-1168).
Other pharmaceutical methods for treating erectile dysfunction have also proved to be problematic. For example, with Viagra.RTM., the most recently introduced oral drug therapy, not only have significant side effects been encountered, but interaction with other systemically administered medications has posed enormous risks and numerous fatalities have in fact been reported.
The invention described herein provides a means to avoid the above-mentioned problems encountered with the systemic administration of pharmacologically active agents to treat erectile dysfunction. Specifically, the invention relates to methods and formulations for effectively treating erectile dysfunction by locally administering a selected active agent, wherein the active agent is an inhibitor of a phosphodiesterase.
Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the metabolism of the second messenger nucleotides, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP) (see, e.g., Doherty, "Oral, Transdermal and Transurethral Therapies for Erectile Dysfunction" in Male Infertility and Dysfunction, Hellstrom, ed., Chapter 34 (New York, N.Y.: Springer-Verlag, 1997)). Numerous phosphodiesterase inhibitors have previously been described in the literature for a variety of therapeutic uses, including treatment of obstructive lung disease, allergies, hypertension, angina, congestive heart failure and depression (see, e.g., Goodman and Gilman's The Pharmacological Basis of Therapeutic Ninth Edition, Chapter 34). Oral and parenteral administration of phosphodiesterase inhibitors, as alluded to above, have also been suggested for the treatment of erectile dysfunction (Doherty, supra; see also PCT Publication Nos. WO 96/16644 and WO 94/28902).
As explained by Komas et al. in Phosphodiesterase Inhibitors, Eds. Schudt et al., Ch. 6 (San Diego, Calif.: Academic Press, 1996), those initially working in the field partially purified what was believed to be a single enzyme responsible for specifically hydrolyzing the 3'-bond of cyclic nucleotides. However, it later became clear that multiple forms of phosphodiesterase inhibitors were present in different tissues; the enzymes were classified into three major groups, one of which exhibited high affinity for cAMP and designated as the "low K.sub.m " cAMP PDE. This "low K.sub.m " cAMP PDE was ultimately discovered to consist of two distinct isoenzymes having entirely different properties, including physical properties, kinetic characteristics and inhibitor specificities. One isoenzyme was found to be very sensitive to inhibition by cilostamide and cGMP, and is now known as the cAMP-specific, cGMP-inhibited cyclic nucleotide phosphodiesterase (cGI-PDE) or PDE III, while the second isoenzyme was classified as PDE IV. Komas et al., supra.
The phosphodiesterases have now been classified into ten major families, Types I-X, based on amino acid or DNA sequences. The members of the family vary in their tissue, cellular and subcellular distribution, as well as their links to cAMP and cGMP pathways. For example, the corpora cavernosa contains: Type III phosphodiesterases, which as explained above are cAMP-specific cGMP inhibitable; Type IV phosphodiesterases, the high affinity, high-specificity cAMP-specific form; and Type V phosphodiesterases, one of the cGMP-specific forms.
Various compounds are known as inhibitors of phosphodiesterases, including vinpocetine, milrinone, amrinone, pimobendan, cilostamide, enoximone, piroximone, vesnarinone, rolipram, RO20-1724, zaprinast, dipyridamole, pentoxifylline, sildenafil citrate (Viagra.RTM.), doxazosin, papaverine, prazosin, terazosin, trimazosin and hydralazine. PCT Publication No. WO 94/28902 discloses a series of pyrazole [4,3-d]pyrimidin-7-ones cGMP phosphodiesterase inhibitors. PCT Publication No. WO 96/16644 also discloses a variety of cGMP phosphodiesterase inhibitors, including griseolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and condensed pyrimidines, a pyrimdopyrimidine derivative, a purine compound, a quinazoline compound, a phenylpyrimidone derivative, an imidazoquinoxalinone derivative or aza analogues thereof, a phenylpyridone derivative, and others.
The following documents are of interest insofar as they relate to the treatment of erectile dysfunction by delivering pharmacologically active agents locally to the penis:
U.S. Pat. No. 4,127,118 to Latorre describes the injection of vasodilator drugs into the corpora cavernosa of the penis to dilate the arteries that supply blood to the erectile tissues, thereby inducing an erection;
U.S. Pat. No. 5,439,938 to Snyder et al. describes the administration of nitric oxide (NO) synthase inhibitors by direct injection of a drug into the corpora cavernosa, by topical drug administration or transurethral drug administration, for inhibiting penile erection due to priapism and for treating urinary incontinence;
Virag et al., Angiology-Journal of Vascular Diseases (February 1984), pp. 79-87, Brindley, Brit. J Psychiat. 143:332-337 (1983) and Stief et al., Urology XXXI:483-485 (1988) respectively describe the intracavernosal injection of papaverine (a smooth muscle relaxant), phenoxybenzamine or phentolamine (.alpha.-receptor blockers) and a phentolamine-papaverine mixture to treat erectile dysfunction; and
PCT Publication No. WO 91/16021, U.S. Pat. No. 4,801,587 to Voss et al., and U.S. Pat. Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020 to Place et al. relate to the treatment of erectile dysfunction by delivery of a vasoactive agent into the male urethra.
The invention, as noted above, is directed to local administration of pharmacologically active agents to treat erectile dysfunction. The active agents are Type III phosphodiesterase inhibitors. Surprisingly, it has now been found by the inventors herein that local administration of these phosphodiesterase inhibitors is highly effective in treating erectile dysfunction, e.g., vasculogenic impotence. Local administration of Type III phosphodiesterase inhibitors, and transurethral administration in particular, generally enables use of a lower drug dosage, avoids many of the side effects encountered with other modes of administration, and avoids interaction with other systemically administered medications an individual may be taking. The local administration of Type III phosphodiesterase inhibitors accordingly represents an important advance in the treatment of impotence and other erectile disorders.